Azetidine → N-[6-(Azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

Temperature

100 °C

4.2 ml (4.2 mmol) of a 1M solution of lithium bistrimethylsilylamide in tetrahydrofuran are added to a mixture, stirred to 0° C. under an argon atmosphere, of 0.7 g (1.76 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide, prepared in step 3.1, of 0.123 g (2.11 mmol) of azetidine, of 8 mg (0.04 mmol) of palladium diacetate and of 19.5 mg (0.04 mmol) of (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine in 1.8 ml of dry and degassed dimethoxyethane. The reactor is closed and then heated at 100° C. for 16 hours. The reaction mixture is then poured into 50 ml of water. 5 ml of a molar solution of hydrochloric acid and then 50 ml of a saturated sodium hydrogencarbonate solution are added slowly. The mixture is extracted twice with 50 ml of ethyl acetate. The organic phases are combined and then washed twice with 50 ml of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and then concentrated under reduced pressure. The product obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and acetone. The resulting solid is then triturated in 20 ml of hot isopropanol, recovered by filtration, and then recrystallized from a mixture of ethanol and methanol. 0.31 g of a solid is recovered by filtration, and dried under reduced pressure.

1. customof dry
2. customdegassed dimethoxyethane
3. customThe reactor is closed
4. additionThe reaction mixture is then poured into 50 ml of water
5. addition5 ml of a molar solution of hydrochloric acid and then 50 ml of a saturated sodium hydrogencarbonate solution are added slowly
6. extractionThe mixture is extracted twice with 50 ml of ethyl acetate
7. washwashed twice with 50 ml of a saturated sodium hydrogen carbonate solution
8. dry with materialdried over magnesium sulfate
9. concentrationconcentrated under reduced pressure
10. customThe product obtained
11. customis purified by silica column chromatography, elution
12. additionbeing carried out with a mixture of dichloromethane and acetone
13. customThe resulting solid is then triturated in 20 ml of hot isopropanol
14. filtrationrecovered by filtration
15. customrecrystallized from a mixture of ethanol and methanol
16. filtration0.31 g of a solid is recovered by filtration
17. customdried under reduced pressure

ORD record

ord-da82c42def4f472eac2b047cd36e69fe

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08586573B2